Etentamig With Step-Up Dosing Shows Preliminary Efficacy, Safety in R/R Myeloma

A step-up dosing strategy for the BCMA x CD3 bispecific antibody etentamig (ABBV-383) generated responses and had a manageable safety profile in patients with relapsed/refractory multiple myeloma, according to findings from a phase 1b study (NCT05650632) presented at the 2024 ASH Annual Meeting.

Data showed patients treated with etentamig across dose-optimization and -expansion cohorts (n = 70) achieved an overall response rate (ORR) of 69%, including 56% of patients who experienced a very good partial response (VGPR) or better. The rates of stringent complete response (CR) or CR, VGPR, and PR were 20%, 36%, and 13%, respectively. Among those receiving the 2-mg step-up dose-optimization regimen (n = 26), the ORR was 73% with all responders achieving a VGPR. The ORRs in the 4-mg step-up dose-optimization cohort (n = 21) and 2-mg step-up dose-expansion cohort (n = 23) were 67% and 65%, respectively. The respective VGPR or better rates in this cohorts were 53% and 39%.

Cytokine release syndrome (CRS) at any grade occurred in 40% of all patients, and the rate of grade 3/4 CRS was 1%. Notably, any-grade CRS occurred in 30% of patients in the 2-mg dose-expansion cohort who also received 36 mg of dexamethasone premedication compared with 10 mg administered in the dose-optimization cohorts; 26% had grade 1 CRS, and 4% had grade 2 CRS. In the dose-expansion cohort, the median time to CRS onset was 22 hours (range, 6-30), and the median resolution time was 21 hours (range, 2-132). No patients had recurrent CRS in 2 or more cycles, and tocilizumab was administered in 9% of patients.

“What we learned from this strategy is that [the 2-mg step-up dose-expansion regimen] yielded a very low overall CRS rate of 30%...without any grade 3 or higher CRS,” study coauthor Muhamed Baljevic, MD, said in an interview with OncLive®. “This is impressive because this is the lowest overall CRS rate [reported thus far for] any bispecific antibody in any step-up schedule that solely relies on dexamethasone premedication.”

Baljevic is an associate professor of medicine in the Division of Hematology Oncology, director of Plasma Cell Disorders Research, director of the Vanderbilt Amyloidosis Multidisciplinary Program, and co-chair of the VICC Protocol Review and Monitoring System at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Phase 1b Study Design and Patient Enrollment Criteria

Previously reported data from a first-in-human phase 1 trial (NCT03933735) showed that patients with relapsed/refractory multiple myeloma treated with etentamig at 60 mg once every 4 weeks experienced an ORR of 65%. During that study, the introduction of modified, higher dexamethasone premedication during cycle 1 reduced the incidence of any-grade CRS from 71% to 43%.

In the open-label phase 1b trial, investigators sought to evaluate a step-up dosing strategy along with dexamethasone premedication. They enrolled patients at least 18 years of age with relapsed/refractory multiple myeloma who had received at least 3 prior lines of therapy, including exposure to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Eligible patients were required to have documented disease progression during or after their last treatment, an ECOG performance status of 0 to 2, and no prior exposure to BCMA-targeted therapy.

All enrolled patients received etentamig in a step-up dosing regimen. In the dose-optimization cohorts, patients received either 2 mg of etentamig with 10 mg dexamethasone premedication on day 1 of cycle 1, followed by 60 mg of etentamig and 10 mg of dexamethasone on day 4 of cycle 1; or 4 mg of etentamig on day 1 of cycle 1, then 60 mg on day 4 of cycle 1 with the same dexamethasone premedication.

In the dose-expansion cohort, patients received 2 mg of etentamig with 10 mg dexamethasone on day 1 of cycle 1, followed by a full 60-mg dose with 36 mg of dexamethasone premedication on day 4 of cycle 1. Starting in cycle 2 for all cohorts, etentamig was administered at 60 mg once every 4 weeks until disease progression, patient withdrawal, or other discontinuation criteria were met.

“This is a very convenient step-up dosing schedule for these patients,” Baljevic noted.

The primary end point of the trial was the incidence of grade 2 or higher CRS during cycle 1. Secondary and exploratory end points included the incidence of any-grade CRS, rates of treatment-emergent adverse effects (TEAEs), immune pharmacodynamics, and clinical activity.

Patient Demographics

Enrolled patients across all 3 cohorts had a median age of 69 years (range, 40-84). The study population was 59% male and 41% female. Patients were White (81%), Black or African American (14%), Asian (4%), or had missing race data (1%).

Geographically, 59% of patients were from North America, 29% were from Asia, and 13% were from other regions. At baseline, 34% of patients had an ECOG performance status of 0, 63% had an ECOG performance status of 1, and 3% had an ECOG performance status of 2.

Most patients (54%) had Revised International Staging System (R-ISS) stage II disease at study entry; 23%, 17%, and 6% had stage I, stage III, and unknown R-ISS stage, respectively. Patients had received a median of 4 prior lines of therapy (range, 3-10). Additionally, 56% of patients had relapsed disease, 44% had refractory disease, 76% were triple-class refractory, and 31% were penta-refractory.

At a median follow-up of 7.2 months (range, 1-14), 57% of patients were ongoing with study treatment. Reasons for treatment discontinuation included disease progression (31%), AEs (6%), withdrawal (1%), and other (4%). The median duration of treatment was 6.7 months (range, 1-15), and the median relative dose intensity was 100% (range, 80%-200%).

Safety Considerations

Any-grade TEAEs occurred in 99% of patients, and 73% had grade 3/4 TEAEs. Serious AEs were reported in 51% of patients. TEAEs led to treatment interruption in 51% of patients and treatment discontinuation in 4% of patients. Six TEAEs led to death, including sepsis (n = 2), disease progression (n = 2), unknown cause (n =1), and COVID-19 pneumonia (n = 1), the latter of which was deemed possibly related to etentamig.

Immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 10% of patients at any grade, and 4% experienced grade 3 ICANS. The median time to the onset of ICANS was 17.1 hours (range, 4.9-68.1), and the median time to resolution was 24.0 hours (range, 7.8-61.2).

The other most common TEAEs beyond CRS and ICANS comprised neutropenia (any-grade, 53%; grade 3/4, 44%), anemia (27%; 20%), thrombocytopenia (17%; 13%), diarrhea (31%; 1%), pneumonia (24%; 17%), fatigue (23%; 0%), cough (20%; 0%), and upper respiratory infection (16%; 1%).

Reference

Mian H, Baljevic M, Magen H, et al. A phase 1b study of step-up dosing with ABBV-383, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma. Blood. 2024;144(suppl 1):1985. doi:10.1182/blood-2024-206912